Field of the Invention
The invention relates generally to cancer, and more particularly to use of genetically modified non-human animal models for screening for agents for use in treating hepatocellular carcinoma.
Background Information
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and a leading cause of cancer deaths. A common malignancy linked to chronic tissue damage, stress, and environmental carcinogen exposure is HCC, most of which arises as the end stage of chronic liver disease and persistent inflammation, with hepatitis B or C virus (HBV, HCV) infections being the current leading causes. However, obesity and alcohol consumption, which cause hepatic steatosis (non-alcoholic steatohepatitis (NASH) or alcoholic steatohepatitis (ASH), respectively) and fibrosis, are rapidly growing in their importance as HCC risk factors.
Thus, more than 90% of HCC develops in the context of chronic liver disease, with HBV or HCV infections being the main causes. However, 30-40% of Western HCC patients do not exhibit viral infections. Most of these patients are obese with manifestations of the metabolic syndrome, and suffer from NASH, a severe form of non-alcoholic fatty liver disease (NAFLD) (Cohen et al., 2011). Indeed, obesity increases male HCC risk by up to 4.5-fold (Calle et al., 2005) and also increases HCC risk in viral hepatitis (Chen et al., 2008). Because the prevalence of obesity has been increasing worldwide, its association with hepatocarcinogenesis has attracted much attention. A need therefore exists for an animal model to study the development of NASH and its progression to HCC, and to test/evaluate treatments that prevent or ameliorate NASH and attenuate its progression to HCC.